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The pathogenic mechanism of syndactyly type V identified in aHoxd13Q50R knock-in mice

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Bone Research 2024年第2期12卷 349-360页

作者： Han Wang Xiumin Chen Xiaolu Meng Yixuan Cao Shirui Han Keqiang Liu Ximeng Zhao Xiuli Zhao Xue Zhang McKusick-Zhang Center for Genetic Medicine State Key Laboratory of Complex Severe and Rare DiseasesDepartment of Medical GeneticsInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Department of Orthopedics State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) ofHOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlyingpathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed togenerate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly andpartial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in *** on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limbdevelopment, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud atE10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibitednotable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involvedin various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopicexpression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both theanterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascadeultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations inhomozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may beresponsible for the manifestation of human SDTY5.

关键词： BMP2 mechanism finding

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Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

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Journal of Genetics and Genomics 2024年第8期51卷 801-810页

作者： Wan-Bing Sun Jing-Xin Fu Yu-Lan Chen Hong-Fu Li Zhi-Ying Wu Dian-Fu Chen Department of Medical Genetics and Center for rare diseases and Department of Neurologyand Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation in Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Nanhu Brain-computer Interface Institute HangzhouZhejiang 314050China MOE Frontier Science Center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310012China

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelα*** variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD *** the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese *** proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as *** pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic *** reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to ***,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.

关键词： Paroxysmal kinesigenic dyskinesia KCNA1 Loss-of-function Gain-of-function Channelopathy Episodicataxiatype1

Haploinsufficiency of Lipin3 leads to hypertriglyceridemia and obesity by disrupting the expression and nucleocytoplasmic localization of Lipin1

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Frontiers of Medicine 2024年第1期18卷 180-191页

作者： Fang Wang Yuxing Liu Yi Dong Meifang Zhao Hao Huang Jieyuan Jin Liangliang Fan Rong Xiang Department of Endocrinology The Third Xiangya Hospital of Central South UniversityChangsha410013China Department of Cellular Biology School of Life SciencesKey Laboratory of Pediatric Rare DiseasesMinistry of EducationCentral South UniversityChangsha410013China

Lipin proteins including Lipin 1–3 act as transcriptional co-activators and phosphatidic acid phosphohydrolase enzymes,which play crucial roles in lipid ***,little is known about the function of Lipin3 in triglyceride(TG)***,we identified a novel mutation(NM_001301860:p.1835A>T/p.D612V)of Lipin3 in a large family with hypertriglyceridemia(HTG)and obesity through whole-exome sequencing and Sanger *** studies revealed that the novel variant altered the half-life and stability of the Lipin3 ***,we generated Lipin3 heterozygous knockout(Lipin3-heKO)mice and cultured primary hepatocytes to explore the pathophysiological roles of Lipin3 in TG *** found that Lipin3-heKO mice exhibited obvious obesity,HTG,and non-alcoholic fatty liver *** study demonstrated that the haploinsufficiency of Lipin3 in primary hepatocytes may induce the overexpression and abnormal distribution of Lipin1 in cytosol and *** increased expression of Lipin1 in cytosol may contribute to TG anabolism,and the decreased Lipin1 in nucleoplasm can reduce PGC1α,further leading to mitochondrial dysfunction and reduced TG *** study suggested that Lipin3 was a novel disease-causing gene inducing obesity and *** also established a relationship between Lipin3 and mitochondrial dysfunction.

关键词： Lipin3 Lipin1 hypertriglyceridemia obesity mitochondrial dysfunction

Resection of polyps involving the appendiceal orifice by combined endo-laparoscopic surgery: Two case reports

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World Journal of Gastrointestinal Surgery 2024年第6期16卷 1948-1952页

作者： Yue-Yi Zhang Jun-Yang Lu Qiang Wang Ai-Ming Yang Department of Gastroenterology State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of General Surgery State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

BACKGROUND The management of polyps involving the appendiceal orifice(AO)presents notable *** resection is frequently hindered by operational complexities,a heightened risk of incomplete removal,and an elevated risk of procedural complications,including ***,surgical resection may entail unnecessary excision of intestinal segments,leading to potential *** SUMMARY Here,we reported two patients who presented with polyps deeply situated within the AO,with indistinct boundaries making it challenging to ensure completeness using traditional endoscopic *** overcome these challenges,we em-ployed combined endo-laparoscopic surgery(CELS),achieving curative resection without postoperative *** The application of CELS in managing polyps involving the AO is emerging as a safe and effective treatment modality.

关键词： Polyps Laterally spreading tumor Appendiceal orifice Endoscopic resection Combined endo-laparoscopic surgery Case report

A novel structural variant of RET causes familial Hirschsprung's disease via nonsense-mediated mRNA decay

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Genes & diseases 2024年第1期11卷 7-10页

作者： Qi Wang Siyu Pu Bo Xiang Jing Chen Department of Pediatric Surgery and Laboratory of Pediatric Surgery Rare Diseases CenterInstitute of Immunology and InflammationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610041China

Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract,leading to the dysregulation of smooth muscle contraction/relaxation and resulting in intestinal *** on the length of the aganglionic intestine,HSCR can be categorized into short-segmental HSCR(S-HSCR),which affects up to the sigmoid colon from the anus,and long-segmental HSCR(LHSCR),which affects beyond the sigmoid colon.1 In some rare conditions,aganglionic lesions can affect the full length of the colon or even the whole intestine.

关键词： intestine colon relaxation

Chinese patients with adult onset leukodystrophy caused by CST3 variants

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Journal of Genetics and Genomics 2024年第7期51卷 778-780页

作者： Yi Zhang Zhi-Ying Wu Department of Medical Genetics and Center for rare diseases Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical TranslationSecond Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Nanhu Brain-computer Interface Institute HangzhouZhejiang 314050China Department of Neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China MOE Frontier Science Center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310012China

Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia *** disorders are clinically diverse and display significant genetic *** is challenging to differentiate hereditary leukodystrophies,particularly those that present in adulthood,from acquired leukodystrophies and other genetic disorders,such as multiple sclerosis(MS)or hereditary spastic paraplegia(HSP)(Wei et al.,2021).Over the past few decades,a series of causative genes associated with leukodystrophies have been identified(Kohler et al.,2018).Nevertheless,a significant proportion of patients still lack a precise molecular diagnosis.

关键词： al. patients Kohler

Chinese consensus on the diagnosis and treatment of immunoglobulin light-chain cardiac amyloidosis

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Chinese Medical Journal 2024年第2期137卷 127-129页

作者： Kaini Shen Zhuang Tian Yajuan Gao Yining Wang Li Huo Jian Li Yun Zhang Shuyang Zhang On behalf of Chinese Society of rare diseases and rare diseases Branch of China Research Hospital Association Department of Hematology State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Cardiology State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Clinical Medicine Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Radiology State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Nuclear Medicine Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear MedicineState Key Laboratory of Complex Severe and Rare DiseasesCenter for Rare Diseases ResearchPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Cardiology The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanShandong 250012China Cardiovascular Disease Research Center of Shandong First Medical University Central Hospital Affiliated to Shandong First Medical UniversityJinanShandong 250013China 不详

Epidemiology of Amyloid Light-Chain Cardiac Amyloidosis(AL-CA)The annual incidence of amyloid light-chain(AL)amyloidosis is 3-5/million,and the incidence in men is slightly higher than that in ***,70%of patients with ... 详细信息

关键词： amyloid cardiac diagnosis

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Comparison of clinical features and outcomes of proliferative,fibrotic,and mixed subtypes of IgG4-related disease:A retrospective cohort study

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Chinese Medical Journal 2024年第3期137卷 303-311页

作者： Linyi Peng Xinlu Zhang Jiaxin Zhou Jieqiong Li Zheng Liu Hui Lu Yu Peng Yunyun Fei Yan Zhao Xiaofeng Zeng Wen Zhang Department of Rheumatology and Clinical Immunology Peking Union Medical College HospitalNational Clinical Research Center for Dermatologic and Immunologic DiseasesState Key Laboratory of Complex Severe and Rare DiseasesThe Ministry of Education Key LaboratoryBeijing 100730China Institute of Clinical Medicine Peking Union Medical College Hospital(PUMCH)Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human ***4-RD can be categorized into proliferative and fibrotic subtypes based on patients’clinicopathological *** study aimed to compare the clinical manifestations,laboratory findings,and treatment outcomes of IgG4-RD among different ***:We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August *** patients were divided into three groups according to their clinicopathological characteristics:proliferative,fibrotic,and mixed *** compared demographic features,clinical manifestations,organ involvement,laboratory tests,and treatment agents across three *** then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with ***,risk factors of relapse were revealed by applying the univariate and multivariate Cox regression ***:We classified the 622 patients into three groups consisting of 470 proliferative patients,55 fibrotic patients,and 97 mixed patients,*** found that gender distribution,age,disease duration,and frequency of allergy history were significantly different among *** terms of organ involvement,submandibular and lacrimal glands were frequently involved in the proliferative subtype,while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed *** comparison of laboratory tests revealed that eosinophils(P=0.010),total IgE(P=0.006),high-sensitivity C-reactive protein(P<0.001),erythrocyte sedimentation rate(P<0.001),complement C4(P<0.001),IgG(P=0.001),IgG1(P<0.001),IgG4(P<0.001),and IgA(P<0.001),at baseline were significantly different among three *** with proliferative and mixed subtypes,the fibrotic subtype showed the

关键词： IgG4-related disease Proliferative subtype Fibrotic subtype Clinical features Treatment outcome

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Insights on ZEB1-AS1: emerging role from cancer to neurodegeneration

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Neural Regeneration Research 2024年第6期19卷 1187-1188页

作者： Stephana Carelli Federica Rey Erika Maghraby Cristina Cereda Pediatric Research Center “Romeo ed Enrica Invernizzi” Department of Biomedical and Clinical Sciences University of Milan 2. Center of Functional Genomics and Rare Diseases Department of Pediatrics Buzzi Children's Hospital Department of Biology and Biotechnology “L.Spallanzani” University of Pavia

Implications for lncRNAs in the central nervous system: Transcriptional dysregulation is a key contributor to the pathogenesis of a wide range of diseases and long non-coding RNAs(lncRNAs) are highly expressed in the nervous system. Indeed, amongst the over 50,000 lncRNAs expressed in the human genome, more than 40% are specifically expressed in the brain where their roles in brain development, neuron functions, maintenance,

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